The present invention relates to fluorinated sulfoxides and to a facile and environmentally acceptable method of oxidizing primary and secondary alcohols to aldehydes and ketones, respectively. More particularly, the invention relates to the oxidation of alcohols using a recyclable, fluorous sulfoxide.
The controlled oxidation of primary and secondary alcohols to aldehydes and ketones, respectively, is one of the most common transformations in organic chemistry. It is not surprising, therefore, that methods of performing such oxidations are consistently being refined and improved. Major advances in recent years include use of a catalytic tetrapropylammonium perruthenate oxidant and the use of 2-iodoxybenzoic acid.
A wide variety of other reagents are utilized in the oxidation of primary and secondary alcohols. However, many of these reagents are metal based and, because of toxicity and environmental concerns, are becoming increasingly unsuitable for use in industrial applications. This is especially the case in the manufacture of fine chemicals and pharmaceuticals wherein, aside from the usual problems of waste disposal, even trace amounts of toxic transition metal salts in the reaction product are unacceptable. The high level of interest in environmentally friendly oxidations is illustrated by the recent number of publications directed to transition metal catalyzed processes with molecular oxygen.
One of the more popular alcohol oxidation methods is the Swern oxidation, which employs a combination of dimethyl sulfoxide, oxalyl chloride, and an organic base. In particular, the Swern oxidation is widely used in the manufacture of fine chemicals, especially pharmaceuticals, because the reaction is metal free and relatively inexpensive. However, a stoichiometric by-product of the Swern oxidation is dimethyl sulfide, which is an extremely volatile (b.p. 37xc2x0 C.) and foul-smelling compound. The generation of dimethyl sulfide also is environmentally unacceptable, which makes the Swern reaction undesirable for large commercial applications. For example, if used in a large reaction scale, the Swern oxidation process would require scrubbing of the waste stream.
Modification of the Swern oxidation to eliminate the formation of dimethyl sulfide has been addressed by using polymer-supported and extractable nonvolatile reagents. See J. M. Harris et al., J. Org. Chem., 63, p. 2407 (1998), and Y. Liu et al., J. Org. Chem., 61, p. 7856 (1996). Each of these modifications suffers from disadvantages. In particular, in the base soluble sulfoxide method, a competing Pummerer reaction that occurs during the course of the oxidation makes recycling inefficient. The polymer-supported analogs are less than ideal on a large scale because of the considerable bulk of polymer required, and because of the obvious difficulty in monitoring a reoxidation process during recycling. Transition metal catalyzed oxidations using molecular oxygen, while having potential in the large scale oxidations of simple industrial alcohols, are not considered suitable for the oxidation of highly functionalized and sensitive alcohols prepared in the modern pharmaceutical industry.
The present invention is directed to an improved method of oxidizing primary and secondary alcohols, in a large scale, that overcomes the disadvantages associated with prior oxidation methods.
The commercial, environmentally friendly preparation of aldehydes and ketones by oxidation of a primary or secondary alcohol, respectively, has been hindered because of the use of metal-based reactions or the generation of noxious by-products, such as dimethyl sulfide. Therefore, the present invention is directed to a commercial scale method of synthesizing aldehydes and ketones that overcome the environmental and disposal problems associated with prior oxidation methods.
In particular, the present invention is directed to a method of preparing aldehydes and ketones from a primary or secondary alcohol, respectively, using a modification of the Swern reaction. In particular, the Swern reaction is modified by using a fluorous sulfoxide to overcome problems associated with the use of dimethyl sulfoxide in a standard Swern reaction.
The Swern reaction was investigated for modification because of the popularity of the reaction with respect to preparing aldehydes and ketones. An important feature of the investigation was to avoid the generation of environmentally unfriendly dimethyl sulfide.
Accordingly, the present invention is directed to a modified Swern reaction wherein a fluorous sulfoxide is substituted for the dimethyl sulfoxide Swern reagent. In particular, one aspect of the present invention is to provide a fluorous Swern reagent that overcomes the disadvantages associated with dimethyl sulfoxide. The fluorous Swern reagent has a general structural formula (I) 
wherein Rf is a fluorinated hydrocarbon chain containing one to twelve carbon atoms; R is C1-4alkyl or (CH2)nxe2x80x94Rf; and n is an integer 1 to 3.
Another aspect of the present invention is to provide a fluorous Swern reagent of structural formula (I) wherein Rf contains four to ten carbon atoms and, preferably, is perfluorinated; R is C1-4alkyl, preferably, methyl or ethyl; and n is 2.
Another aspect of the present invention is to provide a fluorous Swern reagent that avoids the stoichiometric generation of environmentally unfriendly dimethyl sulfide, incorporates a single, relatively short perfluoroalkyl chain (i.e., four to eight carbon atoms) soluble in fluorinated solvents, and is economical and easy to synthesize.
Yet another aspect of the present invention is to provide a method of preparing an aldehyde or a ketone from a primary or secondary alcohol, respectively, using a fluorous sulfoxide of structural formula (I).
Still another aspect of the present invention is to provide a method of recycling the fluorous sulfoxide of structural formula (I) by separateing and oxidizing a fluorous sulfide generated in the Swern reaction to regenerate the fluorous sulfoxide of structural formula (I).
These and other novel aspect and advantages of the present invention will become apparent from the following detailed description of the preferred embodiments.